Tamboli et al. Natural Immunomodulators Vol 2 | Issue 4 | Oct – Dec 2023 Indian J Pharm Drug Studies | 163 Review Article Natural Immunomodulators: Promising Therapy for Disease Management Muskan Altaf Tamboli, Rutuja Ramdas Bhosale, Naziya Ashpak Tamboli From, Professor & Amp, Department of Pharmacology, Sahydri College of Pharmacy, Methwade, Maharashtra, India ABSTRACT The immune system comprises a complex group of processes that provide defense against diverse pathogens. These defenses can be divided into innate and adaptive immunity, in which specific immune components converge to limit infections. We reviewed currently available experimental and clinical evidence to prove the efficiency, safety, and feasibility of immunomodulation in-vitro and in-vivo. We also reviewed the advantages and limitations of the described techniques. Despite its limitations, immunomodulation is considered as the therapy itself or as an adjunct with promising results and developing potential. Many plants and some phytoconstituents responsible for immunomodulation have been explained. The study also discusses biological screening methods for various plant drugs that focus on revealing the mechanism involved in immunomodulation. Nutraceuticals are essential food constituents that provide nutritional benefits as well as medicinal effects. The benefits of these foods are due to the presence of active compounds such as carotenoids, collagen hydrolysate, and dietary fibers. Key words: Immune system, Immunomodulation, Nutraceutical plants, Anti-inflammatory utraceuticals which have also been called medical foods, designer foods, phytochemicals, functional foods and nutritional supplements, include such everyday products as “bio” yoghurts and fortified breakfast cereals, as well as vitamins, herbal remedies, and even genetically modified foods and supplements. Nutraceuticals may be used to improve health, delay the aging process, prevent chronic diseases, increase life expectancy, or support the structure or function of the body [1]. Immunomodulation is an alteration of the immune system and interfering with its functions; if it results in an enhancement of immune reaction, it is named an immune stimulation which primarily implies stimulation of non-specific system, that is, granulocytes, macrophages, complement, certain T- lymphocytes and different effector substances. Immunosuppression implies mainly to reduce resistance Access this article online Received – 08th Nov 2023 Initial Review – 27th Nov 2023 Accepted – 14th Dec 2023 Quick Response Code against infections, and stress and may occur on account of environmental or chemotherapeutic factors. Immunostimulation and Immunosuppression both need to be tackled to regulate normal immunological functioning. Hence, both immunostimulating and immunosuppressing agents have their standing, and the search for better agents exerting these activities is becoming a field of major interest all over the world [2]. Many immunomodulators in clinical use are cytotoxic drugs with significant adverse effects. To overcome toxicity and existing available cytotoxic drugs there is a need for new immunomodulatory medications. Traditional medicines are the oldest approach for treating and managing any illness without causing severe or minor adverse effects. Further, the search for chemicals of plant origin as fresh lead for the creation of potent and safe immunomodulators is receiving a lot of attention [3]. _________________________________________________ Correspondence to: Muskan Altaf Tamboli, Department of Pharmacology, Sahydri College of Pharmacy, Methwade, Maharashtra, India. Email: muskanatamboli17@gmail.com Tel.: +91 7387963031 N mailto:muskanatamboli17@gmail.com Tamboli et al. Natural Immunomodulators Vol 2 | Issue 4 | Oct – Dec 2023 Indian J Pharm Drug Studies | 164 IMMUNITY The resistance offered by the host to the harmful effect of pathogenic microbial infection is called immunity [4]. Types of Immunity: Broadly speaking, immunity or body defense mechanism is divided into two types, each with humoral and cellular components [5]. Natural or innate immunity is non-specific and is considered the first line of defense without antigenic specificity. It has two major components: a) Humoral: comprised by complement. b) Cellular: consists of neutrophils, macrophages, and natural killer (NK) cells. Specific or adaptive immunity is specific and is characterized by antigenic specificity. It too has two main components: a) Humoral: consisting of antibodies formed by B cells. b) Cellular: mediated by T cells. The various components of both types of immunity are interdependent and interlinked for their function. The mechanisms of innate and adaptive immunity are demonstrated in (Figure 1) [6]. Figure 1 - Mechanism of Innate Immunity and Adaptive Immunity Structure of Immune System [5] Organs of Immune System: Although functioning as a system, the organs of the immune system are distributed at different places in the body. These are as under: a) Primary lymphoid organs: i) Thymus ii) Bone marrow b) Secondary lymphoid organs: i) Lymph nodes ii) Spleen iii) MALT (Mucosa-Associated Lymphoid Tissue) located in the respiratory tract and GIT. Cells of Immune System [5] The cells comprising the immune system are as follows: Lymphocytes: Lymphocyte is the master of the human immune system. Morphologically, lymphocytes appear as a homogeneous group but functionally two major lymphocyte populations, T and B lymphocytes are identified; while a third type, NK cells, comprises a small percentage of circulating lymphocytes having the distinct appearance of large granular lymphocytes [5]. Monocytes and Macrophage: The role of macrophages in inflammation consists of circulating monocytes, organ- specific macrophages, and histiocytic. Circulating monocytes are immature macrophages and constitute about 5% of peripheral leucocytes. They remain in circulation for about 3 days before they enter tissues to become macrophages. The macrophage subpopulations like the dendritic cells found in the lymphoid tissue and Langerhans cells seen in the epidermis, are characterized by the presence of dendritic cytoplasmic processes and are active in the immune system [5]. Mast cells and Basophil: Basophils are a type of circulating granulocytes (0-1%) while mast cells are their counterparts seen in tissues, especially in connective tissue around blood Tamboli et al. Natural Immunomodulators Vol 2 | Issue 4 | Oct – Dec 2023 Indian J Pharm Drug Studies | 165 vessels and in submucosal locations. Basophils and mast cells have IgE surface receptors; thus, on coming in contact with antigen binding to IgE (e.g. allergic reaction to parasites), these cells get activated and release granules i.e. degranulate. These granules contain substances such as histamine platelet-activating factor, heparin, and certain chemical mediators (e.g. prostaglandins, leukotrienes). Mast cells and basophils are thus involved in mediating inflamma- tion in allergic reactions and have a role in wound healing [5]. Neutrophils: Polymorphonuclear neutrophils (PMNs) are normally the most numerous of the circulating leucocytes (40-75%). The cytoplasm of PMNs contains lysosomal granules of three types: primary (azurophilic), secondary, and tertiary. PMNs have similar functions to those of macrophages and are therefore appropriately referred to as ‘macrophages’ owing to their role as the first line of defense against an invading foreign organism in the body. However, these cells have limitations in size and type of organisms to be engulfed e.g. while they are capable of acting against bacteria and small foreign Particulate material but not against viruses and large particles [5]. Eosinophils: Eosinophils are also circulating granulocytes (1-6%). These cells play a role in allergic reactions and intestinal helminthiasis. The granules of eosinophils contain lysosomal enzymes, peroxidases, and chemical mediators of inflammation (e.g. prostaglandins, leukotrienes). On coming in contact with IgE opsonized antigen (e.g. helminths), eosinophils degranulate and release the chemicals stored in granules and incite inflammation [5]. Diseases of Immunity The diseases of the immune system are broadly classified into the following four groups: Immunodeficiency Disorder: Failure or deficiency of the immune system, which normally plays a protective role against infections, manifests in the occurrence of repeated infections in an individual having immunodeficiency disease. Traditionally, immunodeficiency diseases are classified into two types: a. Primary immunodeficiencies: are usually the result of genetic or developmental abnormality of the immune system. b. Secondary immunodeficiencies: arise from acquired suppression of the immune system. Since the first description of primary immunodeficiency by Bruton in 1952, an increasing number of primary and secondary immunodeficiency syndromes have been added to the list, the latest addition being the acquired immunodeficiency syndrome (AIDS) in 1981 [5]. Hypersensitivity Reactions: Hypersensitivity is defined as an exaggerated or inappropriate state of normal immune response with the onset of adverse effects on the body. The lesions of hypersensitivity are a form of antigen-antibody reaction. These lesions are termed hypersensitivity reactions or immunologic tissue injury, of which 4 types I, II, III, and IV. Depending upon the rapidity, duration, and type of the immune response, these 4 types of hypersensitivity reactions are grouped into immediate and delayed types [5]. a. Immediate type in which on the administration of antigen, the reaction occurs immediately (within seconds to minutes). Immune response in this type is mediated largely by humoral antibodies (B cell-mediated). Immediate type of hypersensitivity reactions includes type I, II and III. b. Delayed type in which the reaction is slower in onset and develops within 24-48 hours and the effect is prolonged. It is mediated by the cellular response (T cell-mediated) and it includes Type IV reaction [5]. Mechanisms of Hypersensitivity Reaction: Humans live in an environment teeming with substances capable of producing immunologic responses. Contact with antigens leads not only to the induction of a protective immune response, but also to reaction that can be damaging to tissue Exogenous antigen occur in the dust, pollens, foods, drugs microbiologic agent, chemicals and many blood product used in clinical practice the immune responses that may result from such exogenous antigen take a variety of from ranging from annoying but trivial discomforts, such as itching of skin, to potentially fatal diseases, such as bronchial asthma. The various reactions produced are called hypersensitivity reactions, a tissue injury in the reaction may be caused by humoral or cell-mediated immune mechanisms. Injurious immune reactions may be evoked not only by exogenous environmental antigens, but also by endogenous environmental antigens, but also by endogenous tissue antigens. Some of these immune reactions are triggered by homologous antigens that differ among individuals with different genetic backgrounds. Transfusion reactions and graft rejection are examples of immunologic disorders evoked by homologous antigens. Another category of disorders, those incited by self -, or autologous, antigens, Tamboli et al. Natural Immunomodulators Vol 2 | Issue 4 | Oct – Dec 2023 Indian J Pharm Drug Studies | 166 constitutes the important group of autoimmune diseases (discussed later). These diseases arise because of the emergence of immune responses against self–antigens [6]. Table 1 - Comparative Features of 4 Types of Hypersensitivity Reactions [5] Feature Type I [Anaphylactic, atopic] Type II [Cytotoxic] Type III [Immune-complex, Arthus reaction] Type IV [Delayed hypersensitivity] Definition Rapidly developing immune response in a previously sensitized person Reaction of humoral antibodies that attack cell surface antigen and cause cell lysis Result from deposition of antigen-antibody complexes on tissues Cell-mediated slow and prolonged response Peak action time 15-30 minutes 15-30 minutes Within 6 hours After 24 hours Mediated by IgE antibodies IgG or IgM antibodies IgG or IgM antibodies Cell-mediated Examples i. Systemic anaphylaxis. ii. Local anaphylaxis [hay fever, bronchial asthma, food allergy]. i. Cytotoxic antibodies to blood cells [autoimmune haemolytic anaemia, transfusion reactions]. ii. Cytotoxic antibodies to tissue components [Graves’ disease, myasthenia gravis]. i. immune complex glomerulonephritis. ii. Goodpastures syndrome. iii. Collagen diseases [SLE, rheumataoid arthritis]. iv. PAN. v. Drug-induced vasculitis. i. Reaction against microbacterial antigen [tuberculin reaction, tuberculosis]. ii. Reaction against virus-infected cells. iii. Reaction against tumour cells. Autoimmune Diseases: Autoimmunity is a state in which the body’s immune system fails to distinguish between ‘self’ and ‘non-self’ and reacts by formation of auto-antibodies against one’s tissue antigens. In other words, there is a loss of tolerance to one’s tissues; autoimmunity is the opposite of immune tolerance [5]. Depending upon the type of autoantibody formation, autoimmune diseases are broadly classified into two groups: a. Organ-specific diseases: In these, the autoantibodies formed react specifically against an organ or target tissue component and cause its chronic inflammatory destruction. The tissues affected are endocrine glands (e.g. thyroid, pancreatic islets of Langerhans, and adrenal cortex), alimentary tract, blood cells, and various other tissues and organs. b. Organ non-specific (Systemic) diseases: These are diseases in which several auto-antibodies are formed that react with antigens in many tissues and thus cause systemic lesions e.g. various systemic collagen diseases [5]. Possible immune disorders: These are the disorders in which the immunologic mechanisms are suspected in their etiopathogenesis. A classic example of this group is amyloidosis. Immunomodulators Immunomodulators: are natural or synthetic components that regulate the immune system and induce innate and adaptive defense mechanisms. Immunomodulators are drugs or components that suppress the immune system (immunosuppressants) or stimulate the immune system (immunostimulants) [4]. Classification of Immunomodulators Immunostimulants: immunostimulants are substances that stimulate the immune response or enhance body resistance against various infections by increasing the basal level of immune responses. Immunostimulants are used for the treatment of autoimmune diseases, chronic infections, viral infection, and cancer-like diseases. There are two types of Immunostimulants a. Specific Immunostimulant: It provides antigenic specificity in immune response e.g. antigen, vaccines. b. Non-Specific Immunostimulants: It act irrespective of antigenic specificity to augments immune response of other antigen or stimulate components of the immune system without antigenic specificity e.g. Adjuvants. Figure 2 - Examples of Immunostimulants Tamboli et al. Natural Immunomodulators Vol 2 | Issue 4 | Oct – Dec 2023 Indian J Pharm Drug Studies | 167 Immunosuppression: Immunosuppression is a reduction of the activation or efficacy of the immune system. It is a phenomenon wherein the ability of an organism to form antibodies in response to an antigenic stimulus is reduced or suppressed. This suppression may be the result of a disease that targets the immune system, such as HIV infection or a consequence of pharmaceutical agents used to fight cancer. In some cases, immunosuppression may be deliberately induced. Induction may be required for therapeutic interventions of tissue or organ transplantation to reduce the risk of organ rejection. It is also used for treating graft- versus-host disease after a bone marrow transplant or for treatment of auto-immune diseases such as systemic lupus erythematosus, rheumatoid arthritis, Sjogrens syndrome or Crohn’s disease [4]. Two types of immunosuppression 1. Non-specific immunosuppression: This immunosuppression invariably takes places, particularly in the natural instances related to immune deficiency disorders, or may even be induced by the gradual depletion of lymphoid tissue or by the administration of immunosuppressive drugs. It has been observed adequately that undue radiation exposure gives rise to significant depletion of lymphocytes. 2. Specific immunosuppression: - Specific immunosuppression is usually induced either by antigen or antibody. Azathiopurine and corticosteroid combination therapy is commonly used in tissue transplantation to inhibit cell-mediated immunity [CMI]. Cyclosporine is commonly used in immunosuppressive therapy. The monoclonal antibody [OKT3] is also used as an immunosuppressive agent after organ transplantation in humans [4]. Nutraceuticals: Nutraceuticals is defined as substances that can be considered food or its part which, in addition to their normal nutritional value provide health benefits including prevention of disease or promotion of health. The knowledge about the nutritive value of various food items and their basic chemical roles has increased [4]. Classification of Nutraceuticals 1. Nutraceuticals from food source: Nutraceuticals are obtained from plants, animals and microbial resources and are restricted to them only. Linolenic acid is found in animal flesh and is also synthesized in plants. Choline and aphosphatidyl choline are available in plants, animals, and also in microbes. 2. Nutraceuticals indicating their action of mechanism: Nutraceuticals indicate their pharmacological activities i.e. Anti-oxidants, Anti-inflammatory, Anti-cancer, Anti- bacterial, and Bone Protectives. 3. Nutraceuticals according to their chemical nature: The chemical nature of nutraceuticals is Phenolic compounds, Protein-based Isoprenoids, Carbohydrate derivatives, Fatty acids and structural lipids, microbial, minerals, etc. 4. Nutraceuticals according to their higher contents in specific food items: The food substances used as nutraceuticals contain antioxidants, prebiotics, probiotics omega-3-fatty acids, certains phytochemicals and dietary fibers. Expect probiotics, all these components are present in fruits, vegetables and different types of foods. [4] Advantages of Nutraceuticals a. They are substances like food and not considered drugs so have fewer side effects. b. They are mainly used as preventive are prophylactic to improve medical conditions. c. They have natural ingredients and dietary supplements to balance diet discrepancies. d. They enhance overall health and well-being. e. They are available without prescription means accessible and affordable [9]. Disadvantages of Nutraceuticals a. Quality and Regulation Issues: As compared to pharmaceuticals, nutraceuticals are not regulated very strictly and directly. Some of the health claims made for nutraceuticals may not be scientifically validated. There is a lack of proper regulation for nutraceuticals. b. Bioavailability: Nutraceuticals may have poor bioavailability and data related to pharmacokinetics and pharmacodynamics may not be available in some cases. c. Placebo effect: The body has a mechanism to recover on its own. In such cases, consumers may not use nutraceuticals to treat ailments and have a placebo effect. d. Safety and Interactions: Rarely, nutraceuticals may have some side effects. As there is a lack of appropriate regulations, there may be possible side effects, interaction with other drugs, or maybe in effectiveness in treating disorders [9]. Tamboli et al. Natural Immunomodulators Vol 2 | Issue 4 | Oct – Dec 2023 Indian J Pharm Drug Studies | 168 Table 2 - A brief description of Immunomodulators derived from Nutraceuticals Common Name Botanical name (Family) Part used Chemical constituents Other Biological Activity Ref. no. Tea Camellia sinensis L. (Theaceae) Leaves Epigallocatechin gallate, Quercetin, Gallic acid Anti-Oxidant 25 Tulsi Ocimum sanctum L.(Labiateae) Entire plant Essential Oil such as eugenol,Cavacrol Immunomodulator 8 (14.14) Ginger Zingiber officinale roscoe (Zingiberaceae) Dried Rhizome Camphene, Citral, Borneol, Cineolc Anti-Oxidant 9 (4.39- 4.42) Garlic Allium sativum (Liliaceae) Bulbs Diallyl disulfide, Diallyl trisulfide, Zinc, Vit-A Anti-Oxidant Immunomodulator 9 (4.45- 4.46) Turmeric Curcuma langa (Zingiberaceae) Rhizome Curcumin Hydrophobic Anti-Oxidants Anti- Inflammatory 9 (7.6) Amla Emblica officinalis gaetan (Euphorbiaceae) Fruit Tannins, Punigluconin, pedunculagin Anti-Oxidant 9 (4.50- 4.51) Pepper Piper nigrum (Piperaceae) Fruit Volatile Oil, Guineensine, Limonenecamphene, Eugenol Anti-Oxidant 9 (5.21) Tomato Solanum lycopersicum (Solanaceae) Fruit Lycopen, Lipophilic Anti-Oxidant 9 (6.15) Thyme Thymus vulgaris L. (Labiateae) Leaves Flavonoids, Caffeic acid, Labiatic acid Anti-Oxidant 8 (14.66- 14.67) Spirulina Spirulina plantensis (Oscillatoriceae) Algae Proteinous nitrogen, lipid, Protein, Oleic Immunostimulant 8 (18.9- 18.10) Echinacea Echinacea purpurea (Compositae) Leaf, flower Arabinogalactan Immunostimulant 8 (8.5) Alfalfa Medicago sativa Linn. (Leguminosae) Herb Vit.K, Vit.C, Thiamin, Riboflavin Immunomodulator 9 (4.34- 4.35) Chicory Cichorium intybus L. (Asteraceae) Root Sucrose, Cellulose, Protein, Volatile oil, Chicoric acid Anti-Oxidant, Immunomodulator 9 (4.36- 4.39) Fenugreek (Methi) Trigonella foenumgraceum L (Fabaceae) Herb Ascorbic acid, B Carotene, Fibers, Graicunins Immunomodulator 9 (4.42- 4.44) Amra (mango) Mangifera indica Linn. (Anacardiaceae) Bark Tannin, Catechin, Mangiferin Anti- Oxidant 8 (10.3) Ashoka Saraca indica Linn. (Leguminosae) Dried Stem Bark Tannin, Haematoxylin, Ketosterol, Saponin Immunostimulant 8 (10.14- 10.16) Ginseng Panax ginseng (Araliaceae) Root Ginsenosides, Ginsenine, β- sitosterol Anti-Oxidant, Immnomodulator 8 (9.50- 9.52) Tamboli et al. Natural Immunomodulators Vol 2 | Issue 4 | Oct – Dec 2023 Indian J Pharm Drug Studies | 169 Ashvagandha Withania somnifera dunal (Solanceae) Root Withanolides, Withaferin-A, Amino acids Immunomodulator 9 (4.56- 4.58) Ginkgo Biloba Ginkgo biloba L. (Ginkgoaceae) Leaves Quercitrin, Rutin, Kaempferol, Ginkgolide-A Anti-Oxidant 9 (5.13- 5.14) Shatavari Aspargus racemosus wild (Liliaceae) Root Shathavarin I-IV, Quercetin, Rutin Anti-Oxidant 8 (9.62- 9.63) Milk-Thistle Milk thistle silybum marrianum gaerth (Compositae) Seed Silymarin, Silybin, Silycrystin Anti-Oxidant 8 (9.77- 9.78) Guduchi Tinospora cordifolia , Miers (Menispermaceae) Leave And Stem Tinosporine, Tinosporic acid, Berberine Immunostimulant 8 (9.101- 9.103) Rice Bran Oil Oryza sativa (gramineae) Seed .Fatty acid, Palmitic Acid Anti-Oxidant 8 (11.33- 11.34) Teel (Sesame) Sesamum indicum Linn. (Pedaliaceae) Seed Mucilage, HCl, Fixed oil. Anti-Oxidant, Anti- Inflammatory 7 (220) Wormwood Artemisia annua Linn. (Compositea) Herb Artemisinin Immunosuppressive 10 Beggar-tricks Bidens pilosa L. (Asteraceae) Flower, Leave Polyacetylenes Anti-inflammatory , Immunosuppressive 11 Japanese Summer Grape Fruit Citrus nastudaidai hayata (Rutaceae) Fruit Auraptene, Flavonoids Antioxidant 12 Fig Marigold Carpobrotus edulis L. (Aizoaceae) Flower, Fruit Alkaloids Immunomodulator 13 Cone flower Echinacea angustifolia (Asteraceae) Flower Polysaccharides Immunomodulator 14 Bringraja Eclipta alba L. (Compositae) Leaves Triterpenoids, Glucoside Antioxidant 15 Sahijan Moringa oleifera L. (Moringaceae) Leaves Vit.A, Carotenoids, Saponins Antioxidant 16 Paarijaata Anti Nyctanthes arbortr tristis L. (Oleaceae) Leaf, seed Iridoid glicoside Inflammatory, Antispasmodic 17 Kutki Picrorhiza scrophulariiflora benth (Scrophulariaceae) Root Iridoid glycoside, Amphicoside Antioxidant 18 Roseroot Rhodiola imbricate gray (Crassulaceae) Rhizomes Phenolics Immunostimulating Property 19 Glasswort Salicornia herbacea (Chenopodiaceae) Herb Polysaccharides Immunomodulator 20 White cedar Thuja occidentalis L. (Arborvitae) leaves Polysaccharide Immunomodulator 21 Haussknechtia Haussknechtia elymatica (Apioideae) Herb Phenolics Immunomodulator 22 Tamboli et al. Natural Immunomodulators Vol 2 | Issue 4 | Oct – Dec 2023 Indian J Pharm Drug Studies | 170 Cispanche Cistanche desertisola (Orobalachaceae) Herb Polysaccharide Immunomodulator 23 Brahmi Centella asiatica Linn. (Umbelliferae) Herb Triterpenoids, Saponins Immunomodulator 24 Dragon Head Dracocephalum kotschyi (Lamiaceae) Herb Essential oil Immunomodulator 25 Bay leaves (Tejpata) Cinnomomum tamala (Lauraceae) Leaves Eucalyptol, Terpineol, Eugenol Immunosuppressant 27 Cumin (jira) Cuminum cyminum L. (Apiaceae) Seeds Cymol, Cuminol Immunostimulant, Immunosuppressant 28 Tamarind ( Imali) Tamarindus indica L. (Leguminosae) fruits Compesterol, seven hydrocarbon, acetic acid, tartaric acid Antioxidant, Immunomodulator 29, 30 Black Cumin Nigella sativa L. (Ranunculaceae) Seeds Thymoquinone, Dithymoquinone Immunomodulator 31 Bitter Melon (karela) Momordica charantia L. (Cucurbitaceae) Fruits , Seeds Triterpene, proteid, steroid Antioxidant, Immunostimunt 32 Key lime (lemon) Citrus aurantiifolia Swingle (Rutaceae) Fruits, Leaves Limonene, Linalool, Citronellal Antioxidant 33 Red Spiderling Boerhaavia diffusa L. (Nyctaginaceae) Roots Boerhavia acid , Boeravinone, Palmitic acid Antioxidant 34 Sea buckthorn Hippophae rhamnoides L. (Elaeagnaceae) Leaves, fruits Quercetin derivatives, Hydrocinnamic acid Antioxidant 35 Physic nut Jatropha curcas L. (Euphorbiaceae) Leaves Phenolic acid, Lignans, Coumarins Antioxidant, Immunomodulator 36 Sweet flag Acorus calamus L. (Araceae) Rhizome Asarone, Monoterpene, Acorenone Antioxidant, Immunosuppressive 37 Chemistry of plant-derived immunomodulators 1. Glycosides: These organic compounds from plant and animal sources, upon enzymatic or acid hydrolysis, yield one or more sugar moieties. Chemically, they are the acetals or sugar ethers, formed by the interaction of the hydroxyl groups of the sugar and non-sugar moieties, with the loss of a water molecule. Numerous glycosides have been shown to exert the desired immunomodulatory action [38]. 2. Flavonoids: Chemically, flavonoids have a fifteen- carbon skeleton (C6-C3-C6) which consists of two phenyl rings connected by a three-carbon bridge. Several types of flavonoids exert immunomodulatory activities, including apigenin (3), oligomeric proanthocyanidins (4), isoflavonoids, flavones, and anthocyanidins. Such flavonoids are found in Terminalia Arjuna [38]. 3. Coumarins: These glycosides are derivatives of benzo- a-pyrone (5); the furanocoumarins (6) are formed by fusion of furan ring to a coumarin at either the 6 and 7 position or the 7 and 8 position. These glycosides also exert immunomodulatory activities. These glycosides also exert immunomodulatory activites [39]. 4. Alkaloids: These organic compounds are of natural or synthetic origin, basic in nature, containing one or more nitrogen atoms, normally heterocyclic, of limited distribution and have specific physiological actions on the human or animal body [39]. Figure 3 - Flavonoids showing immunomodulatory activity Tamboli et al. Natural Immunomodulators Vol 2 | Issue 4 | Oct – Dec 2023 Indian J Pharm Drug Studies | 171 Figure 4 – Coumarin Figure 5 - Plant alkaloids with immunomodulatory activity Concept of Rasayana The word Rasayana, a combination of two words (rasa and ayana), refers to nutrition and its transportation throughout the body. Rasayana therapy enhances the qualities of rasa, enriching it with nutrients so one can attain longevity, improved memory and intelligence, freedom from disorder, youthfulness, excellence of hair, complexion and voice, optimum development of physique and sense organs, mastery over phonetics and brilliance. As a dedicated stream of medication for immune promotion, anti-degenerative and rejuvenating health care, the Rasayana therapy of Ayurveda is known to prevent the effects of ageing and improve the quality of life for healthy as well as diseased individuals. Rasayana is helpful to improve immunity and is normally advised during the degenerative phase of life, which starts from around 45 years in both male and female Pharmacology of immunomodulatory activities from putative medicinal plants Mechanism of action of the Rasayanas/ immunomodulators It has been reported that the “Rasayanas” are rejuvenators, and nutritional supplements and possess strong antioxidant activities. They also exert antagonistic action on oxidative stressors, giving rise to the formation of different free radicals. They are used mainly to combat the effects of aging, atherosclerosis, cancer, diabetes, rheumatoid arthritis, autoimmune disease and Parkinson’s disease. The Rasayana herbs seem to operate through immunostimulant, immunoadjuvant, and immunosuppressant activities or by affecting the effector arm of the immune response. [40] Modulation of the immune responses through the stimulatory or suppressive activity of a phyto-extract may help maintain a disease-free state in normal or unhealthy people. Agents that activate host defense mechanisms in the presence of an impaired immune response can provide supportive therapy to conventional chemotherapy. [41] A high degree of cell proliferation renders bone marrow a sensitive target, especially to various cytotoxic drugs. Bone marrow is the organ most affected during any immunosuppression therapy with this class of drugs. Loss of stem cells and the inability of the bone marrow to regenerate new blood cells results in thrombocytopenia and leucopenia. [42] Many studies have reported the identification of immunomodulatory compounds with pharmacological activity and limited toxicity. In this context, ethnopharmacology represents the most important way possible to uncover interesting and therapeutically helpful molecules. The phytochemical analysis of Rasayana plants has revealed a large number of compounds including tannic acid, flavonoids, tocopherol, curcumin, ascorbate, carotenoids, polyphenols, etc., which have been shown to have potent immunomodulatory properties. The herbal mixture preparations of Indian traditional medicine may stimulate immunomodulation due to the content of plants with immunomodulatory properties that probably act synergistically. This hypothesis along with the lack of toxicity can be important to understand their use in the past as well as currently. [43] CONCLUSION The immune system is a complex organ with highly specialized cells and even a circulatory separate from blood vessels. Immunodeficiencies occur when one or more of the components of the immune system are inactive. Immunomodulation is the ruling of immune responses by stimulating them to prevent transmittable diseases or by suppressing them in undesired circumstances. Many proteins, amino acids, and natural compounds have shown a significant ability to regulate immune responses, including interferon-γ (IFN-γ), steroids, and DMG. Several medicinal Tamboli et al. Natural Immunomodulators Vol 2 | Issue 4 | Oct – Dec 2023 Indian J Pharm Drug Studies | 172 plants exhibit not only immunomodulatory activity but also a wide range of antioxidant, anti-inflammatory, and other medicinal activities. New immunomodulatory plants are important for the discovery of drugs with fewer side effects, less costly, more potent, and effective treatments developed for immune and related diseases. ACKNOWLEDGEMENTS I would like to thank Dr. Tamboli N.A, Dr. Tamboli A.M Sir, for providing the necessary facilities during my entire work. 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